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4. Digitalis and Other Positive Inotropic Drugs
Used in Congestive Heart Failure
BG Katzung & WW Parmley
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I. Introduction
1. Pathophysiology and Mechanisms
2. Drug Selection
II. Digitalis
1. Properties
2. Adverse effects
3. Drugs available
III. Other positive inotropic agents
1. Properties
2. Drugs available
Subsets of acute severe congestive heart failure
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INTRODUCTION
In congestive heart failure, cardiac output is inadequate for the
needs of the body. Many of the signs and symptoms of the disease result
from attempts by the body to correct or compensate for the inadequate
peripheral perfusion. Some of these compensatory responses lead to fur-
ther deterioration of cardiac function as described under pathophysiol-
ogy. The positive inotropic agents are described in this chapter. Other
drug groups are briefly reviewed here but are covered in more detail in
other chapters.
Therapeutic Rationale
* Reduce salt and water retention: Diuretics are the first line drugs
for use in most uncomplicated cases of congestive heart failure.
(Restriction of sodium intake is desirable but sometimes difficult to
achieve.) Reduction of blood volume decreases the size of the heart,
allowing it to function on a more favorable portion of the ventricular
function curve, and reduces the intracapillary pressure that leads to
edema. The diuretics are described in more detail in Chapter 13.
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* Increase the force of cardiac contraction: Positive inotropic drugs
such as digitalis glycosides are effective in many cases of chronic
failure and move the heart to a higher ventricular function curve.
They are generally more toxic than the diuretics. Several positive in-
otropic substitutes for digitalis are available for use in special
circumstances. * Reduce vascular tone: Vasodilators reduce the work of
the heart and improve cardiac ejection and tissue perfusion. They are
especially useful in acute failure, eg, that associated with myocar-
dial infarction and severe hypertension. Vasodilators are described
in greater detail in Chapters 2 and 5.
Mechanisms
* Diuretics: The mechanisms by which these drugs act are discussed in
Chapter 6. Their efficacy in congestive heart failure reflects the
magnitude of the salt retention that occurs in failure.
* Positive inotropic drugs:
- Digitalis glycosides: Digitalis drugs act by inhibiting membraneNa,K-
ATPase, thereby causing an increase in intracellular sodium. In-
creased intracellular sodium results in an increase in in tracellular
calcium. The latter ion directly modulates the contractile process.
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- Sympathomimetics: Beta-1 adrenoceptor stimulants such as dobutamine
and dopamine are valuable in some cases of acute failure since they
increase cardiac contractility and cause some vasodilation. In favor-
able cases, increased contractility is not accompanied by significant
tachycardia.
- Amrinone, milrinone, methylxanthines, and other PDE inhibitors:
These drugs cause an increase in cylic AMP by inhibiting cardiac
phosphodiesterase. The increase in cAMP results in an increase in
transmembrane calcium flux and a secondary increase in cardiac con
tractility. The same biochemical action increases cAMP in vascular
smooth muscle and results in vasodilation.
* Vasodilators: Direct-acting agents (eg, nitrates, nitroprusside),
sympathoplegics (eg, prazosin), and angiotensin converting enzyme in-
hibitors (eg, captopril) reduce cardiac workload and increase cardiac
output in failure associated with high vascular pressures. Captopril
also decreases aldosterone levels, thereby reducing salt and water
retention.
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Major indications
* Chronic low output failure: Use an thiazide diuretic ,
digoxin , and if necessary, a vasodilator combination such as
hydralazine (unlabelled use) and isosorbide dinitrate ,
or captopril . Some patients respond better to captopril
than to digoxin as the second line drug.
* Acute, severe failure: See Table .
Other Indications:
* Cardiac arrhythmias: cardiac glycosides are often used in atrial
tachycardias, atrial flutter, and atrial fibrillation to control
ventricular rate. In the case of flutter and fibrillation, glycosides
may also lead to the conversion of the arrhythmia to normal sinus
rhythm.
References:
1. Arnold SB, et al: Long-term digitalis therapy improves left
ventricular function in heart failure. NEJM 1980; 303:1443.
2. Cohn JN (editor): New concepts in the mechanisms and treatment of
congestive heart failure (Symposium). Am J Cardiol 1985; 55: 1A.
(PgDn key for more references)
3. Cohn JN, et al: Effect of vasodilator therapy on mortality in chronic
congestive heart failure. Results of a Veterans Administration
Cooperative study. NEJM 1986; 314: 1547.
4. Digitalis. (Symposium) J Am Coll Cardiol 1985; 5: 1A.
5. Doherty JE: Clinical use of digitalis glycosides. An update. Cardiol-
ogy 1985; 72:225.
6. Franciosa JA, Dunkman WB, Leddy CL: Hemodynamic effects of
vasodilators and long-term response in heart failure. J Am Coll Car-
diol 1984; 3: 1521.
7. Jaski BE, et al: Positive inotropic and vasodilator actions of mil-
rinone in patients with severe congestive heart failure. Dose response
relationships and comparison to nitroprusside. J Clin Invest 1085; 75:
643.
8. Maekawa K, Liang C-S, Hood WB: Comparison of dobutamine and dopamine
in acute myocardial infarction. Effects of systemic hemodynamics,
plasma catecholamines, blood flows and infarct size. Circulation 1983;
67:750.
9. Smith TW, et al: Digitalis glycosides: Mechanisms and manifestations
of toxicity. (in 3 parts) Prog Cardiovasc Dis 1984; 26:413,495; 27:21.
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